A common docking domain in progesterone receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells

Christy R. Hagan, Todd P. Knutson, Carol A. Lange

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Progesterone receptors (PR) are transcription factors relevant to breast cancer biology. Herein, we describe an N-terminal common docking (CD) domain in PR-B, a motif first described in mitogen-activated protein kinases. Binding studies revealed PR-B interacts with dual-specificity phosphatase 6 (DUSP6) via the CD domain. Mutation of the PR-B CD domain (mCD) attenuated cell cycle progression and expression of PR-B target genes (including STAT5A and Wnt1); mCD PR-B failed to undergo phosphorylation on Ser81, a ck2-dependent site required for expression of these genes. PR-B Ser81 phosphorylation was dependent on binding with DUSP6 and required for recruitment of a transcriptional complex consisting of PR-B, DUSP6 and ck2 to an enhancer region upstream of the Wnt1 promoter. STAT5 was present at this site in the absence or presence of progestin. Furthermore, phospho-Ser81 PR-B was recruited to the STAT5A gene upon progestin treatment, suggestive of a feed-forward mechanism. Inhibition of JAK/STAT-signaling blocked progestin-induced STAT5A and Wnt1 expression. Our studies show that DUSP6 serves as a scaffold for ck2-dependent PR-B Ser81 phosphorylation and subsequent PR-B-specific gene selection in coordination with STAT5. Coregulation of select target genes by PR-B and STAT5 is likely a global mechanism required for growth promoting programs relevant to mammary stem cell biology and cancer.

Original languageEnglish (US)
Pages (from-to)8926-8942
Number of pages17
JournalNucleic acids research
Volume41
Issue number19
DOIs
StatePublished - Oct 2013

Bibliographical note

Funding Information:
National Institutes of Health [T32 CA009138 to C.H., 1K99CA166643-01 to C.H., R01 CA159712 to C.L.]; Department of Defense Breast Cancer Research Program [BC085608 to C.H., BC093529 to T.K.]. Funding for open access charge: NIH K99.

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